The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, the alveoli, or deep lung (Critical Reviews in Therapeutic Drug Carrier Systems, 6: 273–313 (1990)).
Delivery of bioactive macromolecules to or via the respiratory tract may be useful for the purposes of prophylaxis and therapy of diseases and disorders of the respiratory tract or pulmonary system. For example, local diseases of the pulmonary system may be associated with local antigens such as microbial antigens (respiratory syncytial virus, influenza virus, Streptococcus), tumor antigens (melanoma associated antigens, Neu-2), and inflammation-associated antigens (CD4, IgE). Further, systemic delivery of bioactive macromolecules via the respiratory tract may be useful for prophylaxis or treatment of certain disorders that affect organs other than the lungs. Such systemic diseases may, for example, be associated with tumor antigens (CD20, CEA) or inflammation related antigens (TNFα).
Drug delivery to or via the respiratory tract is an attractive alternative to oral, transdermal, and parenteral administration because self-administration is simple, the lungs provide a large mucosal surface for drug absorption, there is no first-pass liver effect of absorbed drugs, and there is reduced enzymatic activity and pH mediated drug degradation compared with the oral route. Limited bioavailability of many molecules, including macromolecules, can be achieved via inhalation. As a result, several aerosol formulations of therapeutic drugs are in use or are being tested for delivery to the lung (J. Controlled Release, 28: 79–85 (1994); Pharm. Res., 12(9): 1343–1349 (1995); and Pharm. Res., 13(1): 80–83 (1996)).
Drugs currently administered by inhalation come primarily as liquid aerosol formulations. However, many drugs and excipients, especially macromolecules such as proteins and peptides, are unstable in aqueous environments for extended periods of time (Biotechnol. Bioeng., 37: 177–184 (1991)). This can make storage as a liquid formulation problematic. In addition, protein denaturation can occur during aerosolization with liquid formulations (Pharm. Res., 11: 12–20 (1994)). Considering these and other limitations, dry powder formulations (DPF's) are gaining increased interest as formulations for respiratory delivery (EP 0 611 567 A1). However, among the disadvantages of conventional DPF's is that powders of ultrafine particulates usually have poor flowability and aerosolization properties, leading to relatively low respirable fractions of aerosol, i.e., the fractions of inhaled aerosol that escape deposition in the mouth and throat. Another concern with many aerosols is particulate aggregation caused by particle-particle interactions, such as hydrophobic, electrostatic, and capillary interactions. An effective dry-powder inhalation therapy for both short and long term release of macromolecules, either for local or systemic delivery, requires a powder that displays minimum aggregation, as well as a means of avoiding or suspending the lung's natural clearance mechanisms until drugs have been effectively delivered. However, mere engineering of aerosols for optimal aerodynamic and stability characteristics may not necessarily result in desired drug release profiles.
The human lungs can remove or rapidly degrade hydrolytically cleavable deposited particles over periods ranging from minutes to hours. In the upper airways, ciliated epithelia contribute to “mucociliary clearance,” by which particles are swept from the airways toward the mouth. In the deep lungs, alveolar macrophages are capable of phagocytosing particles soon after their deposition. In fact, some references clearly show that a substantial fraction of macromolecule-loaded particles are scavenged by airway macrophages within 10–60 minutes upon delivery to the respiratory tract (Pharma. Res., 17: 275 (2000)). As the diameter of particles exceeds 3 μm, there is increasingly less phagocytosis by macrophages. However, increasing the particle size also has been found to minimize the probability of particles (possessing standard mass density) entering the airways and penetrating the alveoli due to excessive deposition in the oropharyngeal or nasal regions (J. Aerosol Sci., 17: 811–825 (1986)). These particles that do not penetrate into alveoli are then cleared by the mucociliary system within 10–30 minutes after delivery.
In sum, conventional respiratory tract drug delivery strategies present many difficulties for the delivery of macromolecules, including macromolecule denaturation, excessive loss of inhaled drug in the oropharyngeal cavity through mucociliary clearance, and phagocytosis by lung macrophages. In addition, in contrast to small hydrosoluble drugs, macromolecules have a tendency to interact with certain excipients, resulting in retentive structure that thereby limits bioavailability. Thus, there remains a need for improved respiratory tract drug delivery strategies for delivering macromolecules. More particularly, there is a need for the development of methods and compositions which are capable of delivering bioactive macromolecules in an effective amount into the airways or the alveolar zone of the lung for local and/or systemic delivery of the bioactive macromolecule.
It is therefore an object of the present invention to provide improved methods and compositions for the delivery of macromolecules to or via the respiratory tract. It is a further object of the invention to provide inhaled pharmaceutical formulations which effectively deliver macromolecules to the deep lung. It is another object of the invention to provide methods and compositions for delivering macromolecules to or via the respiratory tract such that the macromolecules exhibit improved local and/or systemic bioavailability. It is yet another object of the invention to provide methods and compositions for delivering macromolecules to or via the respiratory tract such that mucociliary clearance and/or macrophage scavenging are reduced.